The mechanism of de novo expression of programmed cell death-ligand 1 in squamous cell carcinoma of the lung
The mechanism of de novo expression of programmed cell death-ligand 1 in squamous cell carcinoma of the lung
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DOI：
10.3892/or.2017.5876
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发表时间：
2017-10-01
期刊：
影响因子：
4.2
通讯作者：
Daigo, Yataro
中科院分区：
文献类型：
--
作者：
Igarashi, Tomoyuki;Teramoto, Koji;Daigo, Yataro
肿瘤细胞利用免疫检查点机制，如程序性细胞死亡-配体1-程序性细胞死亡1（PD-L1-PD-1）轴，以逃避效应免疫细胞的细胞毒性。然而，负责肿瘤细胞上PD-L1表达的环境因素仍有待充分阐明。我们假设与肿瘤浸润性CD 8（+）淋巴细胞（CD 8（+）TIL）的免疫相互作用将有助于肿瘤细胞中PD-L1的表达。为了验证这一假设，我们检测了干扰素-γ（IFN-γ）（一种由CD 8（+）TIL分泌的细胞因子）对肺鳞状细胞癌中PD-L1表达的影响。我们还通过免疫组化评估了PD-L1和主要组织相容性复合物（MHC）I类分子在肺鳞状细胞癌（n=77）中肿瘤细胞和CD 8（+）TIL上的表达。IFN-γ可上调肺鳞癌细胞PD-L1的表达，且该反应是可逆的。在MHC I类分子阳性肿瘤细胞占优势的病例中（n=72，93.5%），PD-L1阳性肿瘤细胞占优势的病例（PD-L1（+）肿瘤细胞占优势的病例; n=45）比PD-L1阴性肿瘤细胞占优势的病例（n=27）更常见（P=0.006）。PD-L1（+）肿瘤细胞占优势的病例中CD 8（+）TIL数量显著高于PD-L1（-）肿瘤细胞占优势的病例（P=0.005）。这些数据表明，在用MHC I类分子识别肿瘤细胞后，CD 8（+）TILs分泌的IFN-γ上调肿瘤细胞上PD-L1的从头表达。
Immune checkpoint mechanisms such as the programmed cell death-ligand 1-programmed cell death 1 (PD-L1-PD-1) axis are utilized by tumor cells to evade the cytotoxicity of effector immune cells. However, environmental factors responsible for the expression of PD-L1 on tumor cells remain to be fully elucidated. We hypothesized that an immunological interaction with tumor-infiltrating CD8(+) lymphocytes (CD8(+) TILs) would contribute to PD-L1 expression in tumor cells. To verify this hypothesis, we examined the effect of interferon-gamma (IFN-gamma), a cytokine secreted by CD8(+) TILs, on PD-L1 expression in pulmonary squamous cell carcinomas in vitro. We also evaluated the expression of PD-L1 and major histocompatibility complex (MHC) class I molecules on tumor cells and CD8(+) TILs in squamous cell carcinomas of the lung (n=77) by immunohistochemistry. IFN-gamma upregulated PD-L1 expression on pulmonary squamous carcinoma cells, and the reaction was reversible. In cases where which MHC class I molecule-positive tumor cells were dominant (n=72, 93.5%), cases in which PD-L1-positive tumor cells were dominant (PD-L1(+) tumor cell-dominant cases; n=45) were more frequently observed than PD-L1-negative tumor cell-dominant cases (n=27) (P=0.006). The number of CD8(+) TILs was significantly higher in PD-L1(+) tumor cell-dominant cases compared with PD-L1(-) tumor cell-dominant cases (P=0.005). These data suggest that the de novo expression of PD-L1 on tumor cells is upregulated by IFN-gamma secreted from CD8(+) TILs upon recognition of the tumor cells with an MHC class I molecule.